PT  - JOURNAL ARTICLE
AU  - Claudia Kuntner
AU  - Jens Bankstahl
AU  - Aiman Abrahim
AU  - Rudolf Karch
AU  - Johann Stanek
AU  - Thomas Wanek
AU  - Maria Zsebedics
AU  - Wolfgang Wadsak
AU  - Wolfgang Löscher
AU  - Oliver Langer
TI  - P-glycoprotein modulation at the rat blood-brain barrier studied with (R)-[<sup>11</sup>C]verapamil PET
DP  - 2008 May 01
TA  - Journal of Nuclear Medicine
PG  - 210P--210P
VI  - 49
IP  - supplement 1
4099  - http://jnm.snmjournals.org/content/49/supplement_1/210P.4.short
4100  - http://jnm.snmjournals.org/content/49/supplement_1/210P.4.full
SO  - J Nucl Med2008 May 01; 49
AB  - 909 Objectives: To study modulation of the multidrug efflux transporter P-glycoprotein (P-gp) at the rat blood-brain barrier (BBB) by the new-generation P-gp inhibitor tariquidar (TQD) with small-animal PET and (R)-[11C]verapamil (VPM). Methods: 5 Wistar Unilever rats underwent paired VPM PET scans and arterial blood sampling at an interval of 3 hours. At 2 hours before the 2nd PET scan, TQD (15 mg/kg) was administered by i.v. injection. 2 animals underwent test-retest examinations without TQD administration. An additional group of animals underwent single VPM PET scans after administration of 1, 3, 5, and 7.5 mg/kg of TQD. The PET data were analyzed with a 4-rate-constant-2-tissue compartment model. Results: Following TQD administration, the distribution volume DV of VPM was 12-fold higher than at baseline (3.68±0.81 vs. 0.30±0.08; p=0.0007, paired t-test), whereas the DVs were essentially the same in the test-retest examinations. The increase in DV could mainly be attributed to an increased influx rate constant K1 of radioactivity into the brain, which was about 8-fold higher after TQD. The dose-response assessment provided an estimated half-maximum effect dose of 6.5 mg/kg (95% confidence interval, 4.9-8.2) for TQD. VPM metabolism and plasma protein binding were unchanged after TQD administration. Conclusions: Our data suggest that TQD is a potent inhibitor of P-gp at the BBB that enhances intracerebral uptake of P-gp substrates.